The light sensing and signaling processes of the human retina require a high level of support in terms of energy supply and waste removal to ensure optimal functionality. A monolayer of epithelial cells, known as the retinal pigmented epithelium (RPE) separates the light sensing and signaling processes from the blood supply of the choroid and it controls many bi-directional support functions. The RPE cells are attached to a basement membrane, known as Bruch's membrane, which is a thin extra-cellular matrix of collagen layers which acts as a semi-permeable barrier between the RPE cells and blood vessels of the choroid. The work of Marshall, Hussain, et. al. over many years has shown that degradation of the transport functions of Bruch's membrane is a major contributor to loss or decline in visual function with normal aging or a more rapid decline due to diseases such as age-related macular degeneration (AMD) and is well described in the following references:    Starita C., Hussain A. A., Marshall J. (1995). Decreasing hydraulic conductivity of Bruch's membrane: relevance to photoreceptor survival and lipofuscinoses. American Journal of Medical Genetics. 57(2):235-7.    Moore D. J., Hussain A. A., Marshall J. (1995). Age-related variation in the hydraulic conductivity of Bruch's membrane. Investigative Ophthalmology & Visual Science. 36(7):1290-7.    Starita C., Hussain A. A., Pagliarini S., Marshall J. (1996) Hydrodynamics of ageing Bruch's membrane: implications for macular disease. Experimental Eye Research. 62(5):565-72.    Starita C., Hussain A. A., Patmore A., Marshall J. (1997) Localisation of the site of major resistance to fluid transport in Bruch's membrane. Invest. Opthalmol. Vis Sci. 38: 762-767.    Marshall J., Hussain A. A., Starita C., Moore D. J., Patmore A. L. (1998). Ageing and Bruch's membrane. In: Marmor M F ed. Retinal Pigment Epithelium: Function and disease. New York, Oxford University Press; pp. 669-692.    Hussain A A., Rowe L., Marshall J. (2002) Age-related alterations in the diffusional transport of amino acids across the human Bruch's-choroid complex. Journal of the Optical Society of America, A, Optics, Image Science, & Vision. 19(1): 166-72.    Hussain A A., Starita C., and Marshall J. (2004) Chapter IV. Transport characteristics of ageing human Bruch's membrane: Implications for AMD. In Focus on Macular Degeneration Research, (Editor O. R. Ioseliani). Pages 59-113. Nova Science Publishers, Inc. New York.    Guo L., Hussain A A., Limb G A., Marshall J (1999). Age-dependent variation in metalloproteinase activity of isolated human Bruch's membrane and choroid. Investigative Opthalmol. Vis Sci. 40(11): 2676-82.
Although these transport functions begin to degrade from birth, serious vision loss may not occur until later in life when the RPE/Bruch's membrane/choroid complex degrades to a point at which it can no longer sustain the neuro-retina, resulting in atrophy of the neuro-retina or stress induced responses such as choroidal new vessel (CNV) growth.
Although changes in diet and environment have been recommended to reduce the rate of age related loss of visual acuity, no direct treatment exists, and almost all current treatments for AMD are focused on treating late stage complications such as CNV's. Current treatments for CNV's include photo-dynamic therapy (PDT) (as described in U.S. Pat. No. 5,756,541 assigned to QLT phototherapeutics Inc) where a photosensitive drug is administered intravenously and then activated by a light source which is directed at the CNV, and intra-vitreal injections of drugs which inhibit the growth factors which promote new blood vessel growth (anti-VEGF).
In Diabetic Macular Edema (DME) fluid leakage from retinal blood vessels can pool within retinal spaces or between the RPE/photoreceptor interface. If the RPE is unable to remove this fluid due to compromised transport through Bruch's membrane vision loss can occur. Large clinical trials have shown that early laser treatment can reduce the risk of severe vision loss from DME, although the collateral damage caused by current laser treatment makes it unsuitable for treatment near the center of vision (fovea). Intra-vitreal anti-VEGF drugs have recently been used to stop or reduce the leakage however they do not improve the ability to remove existing fluid accumulation.
Lasers have been used for many years to treat retinal disorders, predominately using their ability to coagulate tissue. The degree of laser energy absorption in retinal layers and structures is highly dependant on the wavelength used and one of the major absorbing chromophores within the retina is the melanin which pigments the RPE cells. Although the current retinal lasers use wavelengths that are strongly absorbed by the melanin of the RPE cells, the duration of the laser pulses which are currently used allows time for thermal diffusion from the RPE cells to adjacent structures and is particularly damaging to the neuro-retina resulting in permanent loss of visual function at the treatment site.
Anderson and Parrish introduced the idea of Selective Photothermolysis in April 1983 in the journal Science, Vol 220 in which they taught that suitably brief pulses of selectively absorbed optical radiation can cause selective damage to pigmented structures, cells, and organelles in vivo. A laser device to perform selective photothermolysis was then described in U.S. Pat. No. 5,066,293 filed in March 1989 which included a method of treating vascular lesions. This concept of confining damage by the use of short laser pulses was then applied to retinal treatment by Roider and Birngruber in a paper titled “Spatial confinement of photo-coagulation effects using high repetition rate laser pulses” which was presented at the Conference on Lasers and Electro-Optics in May 1990 and then expanded on by Roider, Norman, Flotte, and Birngruber in a paper titled “Response of the Retinal Pigment Epithelium to Selective Photocoagulation”, Archives of Ophthalmology, Vol 110, December 1992, accepted for publication April 1992 and presented at the annual meeting of the Association for Research in Vision and Ophthalmology in April 1991. In this latter paper an animal experiment was able to demonstrate selective damage to the RPE while largely sparing the overlying photoreceptors. This technique has become known as selective retinal therapy (SRT) and has since been applied to a number of late stage retinal diseases with the aim of producing a therapeutic benefit by forcing RPE cells to migrate and divide, but with limited success. The technique is well described by Lin in United States patent application 20040039378. Roider, Brinkmann, Wirbelauer, Laqua and Birngruber (Subthreshold photocoagulation in macular diseases: a pilot study, Br J. Opthalmol. 2000 January; 84(1):40-7) have carried out small clinical trials to demonstrate that short duration laser pulses can be used to contain the energy within the RPE cells and prevent neuro-retinal damage.
In United States patent application 20050048044, Schwartz describes the need to improve the function of Bruch's membrane, but the method described is similar to PDT in that a drug is administered that can be activated on the target membrane. Once activated the drug has a tissue degrading action on the membrane with the aim of improving it's transport properties.